Abstract
The mechanism underlying the pathogenesis of schizophrenia remains poorly understood. The hyper-dopamine and hypo-NMDA receptor hypotheses have been the most enduring ideas. Recently, emerging evidence implicates alterations of the major inhibitory system, GABAergic neurotransmission in the schizophrenic patients. However, the pathophysiological role of GABAergic system in schizophrenia still remains dubious. In this study, we took advantage of GABA transporter 1 (GAT1) knockout (KO) mouse, a unique animal model with elevated ambient GABA, to study the schizophrenia-related behavioral abnormalities. We found that GAT1 KO mice displayed multiple behavioral abnormalities related to schizophrenic positive, negative and cognitive symptoms. Moreover, GAT1 deficiency did not change the striatal dopamine levels, but significantly enhanced the tonic GABA currents in prefrontal cortex. The GABAA receptor antagonist picrotoxin could effectively ameliorate several behavioral defects of GAT1 KO mice. These results identified a novel function of GAT1, and indicated that the elevated ambient GABA contributed critically to the pathogenesis of schizophrenia. Furthermore, several commonly used antipsychotic drugs were effective in treating the locomotor hyperactivity in GAT1 KO mice, suggesting the utility of GAT1 KO mice as an alternative animal model for studying schizophrenia pathogenesis and developing new antipsychotic drugs.
Highlights
Schizophrenia is a highly debilitating mental disorder that affects approximately 1% of the world’s population, which pathogenesis mechanisms remain unclear
MK801 at 0.3 mg/kg but not 0.1 mg/kg significantly increased the locomotor activity in WT mice (distance traveled in 30 min after drug treatment, saline, 25.961.9 m; MK801 0.1 mg/kg, 28.861.8 m; MK801 0.3 mg/ kg, 113.066.4 m; n = 7–8 for each group, F(2, 19) = 137.9, 0.1 mg/kg vs saline, p.0.1; 0.3 mg/kg vs saline, p,0.01, ANOVA, Fig. 1B1 & 1B3), while in GABA transporter 1 (GAT1) KO mice, MK801 at 0.1 mg/kg was enough to induce locomotor hyperactivity (saline, 47.163.3 m; MK801 0.1 mg/kg, 86.5616.4 m; MK801 0.3 mg/kg, 164.7613.5 m; n = 7–8 for each group, F(2, 20) = 25.7, 0.1 mg/kg vs saline, p = 0.03; 0.3 mg/kg vs saline, p,0.01; genotype6dose interaction, F(2, 39) = 3.1, p = 0.05, ANOVA, Fig. 1B2 & 1B3). Another non-competitive NMDA receptor (NMDAR) antagonist PCP (3 mg/kg) induced locomotor hyperactivity in both WT and GAT1 KO mice (WT, saline, 20.362.4 m, PCP, 55.3610.7 m, F(1, 11) = 11.9, p,0.01; GAT1 KO, saline, 39.663.8 m, PCP, 129.3610.8 m, F(1, 10) = 61.4, p,0.01, n = 6–7 for each group, ANOVA, Fig. 1C), while the stimulant effect was significantly larger in GAT1 KO mice (genotype6dose interaction, F(1, 21) = 12.9, p,0.01, ANOVA, Fig. 1C)
These results indicate that GABAergic antagonism can treat the locomotor hyperactivity and working memory defect in GAT1 KO mice, suggesting that antagonizing GABAergic activity may be a potential strategy for the therapy of schizophrenia
Summary
Schizophrenia is a highly debilitating mental disorder that affects approximately 1% of the world’s population, which pathogenesis mechanisms remain unclear. Postmortem studies report reduced mRNA level and expression of the GABA synthesizing enzyme, 67 kDa isoform of glutamic acid decarboxylase (GAD67), and GAT1, as well as an apparent upregulation of postsynaptic GABAA receptors (GABAARs) in the prefrontal cortex of human subjects with schizophrenia [3], suggesting a mechanism for abnormal GABAergic neurotransmission in schizophrenia. These studies mainly focus on the morphological examinations in individuals with schizophrenia, but the functional study falls far behind. It was supposed in several studies that the GAT1 downregulation may be a compensatory mechanism to the reduction of GABA synthesis [3,21], the functional significance of GAT1 downregulation remains unknown
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